Anti-dll3 antibody and preparation method therefor, drug conjugate and application thereof

Abstract

Disclosed are an anti-DLL3 antibody and a preparation method therefor, a drug conjugate and application thereof. The anti-DLL3 antibody in the present invention has good internalization activity, has better binding activity with human DLL3 protein, and has strong affinity at the protein level. The antibody conjugated drug targeting DLL3 in the present invention has good druggability, biological activity, and anti-tumor activity in vitro and vivo, and can achieve an application of cytotoxic drugs in treating tumor patients comprising SCLC and having neuroendocrine characteristics.

What is claimed is: 
     
         1 . An anti-DLL3 antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL); wherein
 the VH comprises complementarity-determining regions (CDRs) as follows: VH CDR1 as shown in amino acid sequences of SEQ ID NO: 9, 19, 29, 39, 59, 69, 79, 89, 99, or 63, VH CDR2 as shown in amino acid sequences of SEQ ID NO: 10, 20, 30, 40, 60, 70, 80, 90, 100, 110, or 83, and VH CDR3 as shown in amino acid sequences of SEQ ID NO: 11, 21, 31, 41, 61, 71, 81, 91, 101, 111, or 93;   the VL comprises CDRs as follows: VL CDR1 as shown in amino acid sequences of SEQ ID NO: 12, 32, 42, 62, 72, 82, 92, 102, 112, or 103, VL CDR2 as shown in GAS, GAT, TTS, NAK, YTS, RAN, WAS, FTS, or NAN, and VL CDR3 as shown in amino acid sequences of SEQ ID NO: 14, 24, 34, 44, 64, 74, 84, 94, 104, 114, or 113.   
     
     
         2 . The anti-DLL3 antibody according to  claim 1 , wherein amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 9, 10, and 11; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 19, 20, and 21; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 29, 30, and 31; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 39, 40, and 41; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 59, 60, and 61; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 69, 70, and 71; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 79, 80, and 81; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 89, 90, and 91; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 99, 100, and 101; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 89, 110, and 111; or amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 63, 83, and 93;
 amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 12, GAS, and SEQ ID NO: 14; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 12, GAS, and SEQ ID NO: 24; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 32, GAT, and SEQ ID NO: 34; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 42, TTS, and SEQ ID NO: 44; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 62, NAK, and SEQ ID NO: 64; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 72, NAK, and SEQ ID NO: 74; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 82, YTS, and SEQ ID NO: 84; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 92, RAN, and SEQ ID NO: 94; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 102, WAS, and SEQ ID NO: 104; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 112, FTS, and SEQ ID NO: 114; or amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 103, NAN, and 113.   
     
     
         3 . The anti-DLL3 antibody according to  claim 1 or 2 , wherein amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 9, 10, and 11; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 12, GAS, and SEQ ID NO: 14; or
 amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 19, 20, and 21; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 12, GAS, and SEQ ID NO: 24; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 29, 30, and 31; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 32, GAT, and SEQ ID NO: 34; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 39, 40, and 41; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 42, TTS, and SEQ ID NO: 44; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 59, 60, and 61; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 62, NAK, and SEQ ID NO: 64; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 69, 70, and 71; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 72, NAK, and SEQ ID NO: 74; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 79, 80, and 81; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 82, YTS, and SEQ ID NO: 84; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 89, 90, and 91; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 92, RAN, and SEQ ID NO: 94; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 99, 100, and 101; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 102, WAS, and SEQ ID NO: 104; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 89, 110, and 111; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 112, FTS, and SEQ ID NO: 114; or   amino acid sequences of VH CDR1, VH CDR2, and VH CDR3 comprised in the VH are respectively as shown in SEQ ID NO: 63, 83, and 93; and amino acid sequences of VL CDR1, VL CDR2, and VL CDR3 comprised in the VL are respectively as shown in SEQ ID NO: 103, NAN, and 113.   
     
     
         4 . The anti-DLL3 antibody according to any one of  claims 1 to 3 , wherein the heavy chain variable region (VH) further comprises a heavy chain variable region framework region (VH FWR), and/or the light chain variable region (VL) further comprises a light chain variable region framework region (VL FWR); wherein the VH FWR is the heavy chain variable region framework region of a human or murine antibody, and the VL FWR is the light chain variable region framework region of a human or murine antibody;
 preferably:   the VH comprises the amino acid sequence as shown in SEQ ID NO: 15, 25, 35, 45, 65, 75, 85, 95, 105, 13, or 22, and/or the VL comprises the amino acid sequence as shown in SEQ ID NO: 16, 26, 36, 46, 66, 76, 86, 96, 106, 33, or 23;   more preferably:   the VH comprises the amino acid sequence as shown in SEQ ID NO: 15, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 16; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 25, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 26; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 35, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 36; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 45, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 46; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 65, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 66; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 75, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 76; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 85, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 86; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 95, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 96; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 105, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 106; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 13, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 33; or   the VH comprises the amino acid sequence as shown in SEQ ID NO: 22, and the VL comprises the amino acid sequence as shown in SEQ ID NO: 23.   
     
     
         5 . The anti-DLL3 antibody according to any one of  claims 1 to 4 , wherein the anti-DLL3 antibody is a full-length antibody, Fab, Fab′, F(ab′)2, Fv, preferably scFv, a heavy chain antibody, or a single-domain antibody, and/or the anti-DLL3 antibody is a monoclonal antibody, a bispecific antibody, or a multispecific antibody. 
     
     
         6 . The anti-DLL3 antibody according to  claim 5 , wherein the anti-DLL3 antibody is a full-length antibody, and the full-length antibody comprises a heavy chain and a light chain; wherein the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 17, 27, 37, 47, 67, 77, 87, 97, 107, 43, or 73, and/or the light chain comprises the amino acid sequence as shown in SEQ ID NO: 18, 28, 38, 48, 68, 78, 88, 98, 108, 53, or 109;
 preferably:   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 17, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 18; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 27, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 28; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 37, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 38; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 47, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 48; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 67, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 68; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 77, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 78; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 87, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 88; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 97, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 98; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 107, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 108; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 43, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 53; or   the heavy chain comprises the amino acid sequence as shown in SEQ ID NO: 73, and the light chain comprises the amino acid sequence as shown in SEQ ID NO: 109.   
     
     
         7 . An isolated nucleic acid encoding the anti-DLL3 antibody according to any one of  claims 1 to 6 . 
     
     
         8 . A recombinant expression vector comprising the isolated nucleic acid according to  claim 7 ;
 preferably, the expression vector comprises a eukaryotic cell expression vector and/or a prokaryotic cell expression vector.   
     
     
         9 . A transformant comprising the recombinant expression vector according to  claim 8 ;
 preferably, the host cell of the transformant is a prokaryotic and/or a eukaryotic cell, wherein the prokaryotic cell is preferably  E. coli  cell such as TG1 or BL21 cell, and the eukaryotic cell is preferably HEK293 cell or CHO cell.   
     
     
         10 . An antibody-drug conjugate with a general formula: Ab-(L 3 -L 2 -L 1 -D) m ;
 wherein Ab is an anti-DLL3 antibody;   D is a cytotoxic drug   
       
         
           
           
               
               
           
         
         m is 2 to 8; 
         the structure of L1 is as shown in formulas I, II, III, or IV, with a-terminal connected to the cytotoxic drug, and e-terminal connected to c-terminal of the L 2 ; 
       
       
         
           
           
               
               
           
         
         in (L) p , L independently represents one or more of phenylalanine residue, alanine residue, glycine residue, glutamic acid residue, aspartic acid residue, cysteine residue, glutamine residue, histidine residue, isoleucine residue, leucine residue, lysine residue, methionine residue, proline residue, serine residue, threonine residue, tryptophan residue, tyrosine residue, and valine residue; “p” is from 2 to 4. 
         R 1  is C 1 -C 6  alkyl substituted by one or more —NR 1-1 R 1-2 , C 1 -C 6  alkyl substituted by one or more R 1-3 S(O) 2 —, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 6 -C 14  aryl, or 5- to 14-membered heteroaryl; 
         the heteroatom in the 5- to 14-membered heteroaryl is selected from one or more of N, O, and S, and the number of the heteroatom is 1, 2, 3, or 4; the R 1-1 , R 1-2 , and R 1-3  are each independently C 1 -C 6  alkyl; 
         L 2  is 
       
       
         
           
           
               
               
           
         
          wherein n is independently 1 to 12, and c-terminal is connected to L 1  through a carbonyl group, and f-terminal is connected to d-terminal of L 3 ; 
         L 3  is 
       
       
         
           
           
               
               
           
         
          wherein b-terminal is connected to the Ab, and d-terminal is connected to f-terminal of L 2 . 
       
     
     
         11 . The antibody-drug conjugate according to  claim 10 , wherein
 the anti-DLL3 antibody binds to one or more of following antigen-binding epitopes of DLL3 protein: DSL domain, N-terminal, EGF2 domain, and EGF3-EGF6 domain;   and/or L is one or more of phenylalanine residue, alanine residue, glycine residue, isoleucine residue, leucine residue, proline residue, and valine residue; preferably one or more of phenylalanine residue, alanine residue, glycine residue, and valine residue; further preferably, the L is valine residue and/or alanine residue; the “more” means two or three; p is 2;   and/or the R 1  is C 1 -C 6  alkyl substituted by one or more —NR 1-1 R 1-2 , C 1 -C 6  alkyl substituted by one or more R 1-3 S(O) 2 —, or C 1 -C 6  alkyl; the R 1-1 , R 1-2 , and R 1-3  are each independently C 1 -C 4 ;   and/or when the structure of L 1  is as shown in formula I, the L 2  is preferably   
       
         
           
           
               
               
           
         
         and/or when the structure of L 1  is as shown in formula II, the L 2  is preferably 
       
       
         
           
           
               
               
           
         
         and/or when the structure of L 1  is as shown in formula III, the L 2  is preferably 
       
       
         
           
           
               
               
           
         
         and/or when the structure of L 1  is as shown in formula IV, the L 2  is preferably 
       
       
         
           
           
               
               
           
         
         and/or the n is independently 8, 9, 10, 11, and 12; 
         and/or the m is an integer or non-integer from 2 to 8; 
         and/or the L 3  is preferably 
       
       
         
           
           
               
               
           
         
       
     
     
         12 . The antibody-drug conjugate according to  claim 10 or 11 , wherein
 the anti-DLL3 antibody binds to the antigen-binding epitope in the EGF2 domain of DLL3 protein;   and/or the (L) p  is   
       
         
           
           
               
               
           
         
          wherein g-terminal is connected to c-terminal of L 2  through a carbonyl group; 
         and/or the formula III is preferably 
       
       
         
           
           
               
               
           
         
       
     
     
         13 . The antibody-drug conjugate according to  claim 10 , wherein the antibody-drug conjugate is any one of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         the Ab is an anti-DLL3 antibody, wherein the anti-DLL3 antibody is the anti-DLL3 antibody according to any one of  claims 1 to 6 , the anti-DLL3 antibody comprising a light chain with an amino acid sequence as shown in SEQ ID NO: 1 and a heavy chain with an amino acid sequence as shown in SEQ ID NO: 2, or comprising a light chain with an amino acid sequence as shown in SEQ ID NO: 3 and a heavy chain with an amino acid sequence as shown in SEQ ID NO: 4; 
         the m is 7.68, 7.53, 4.43, 7.12, 6.92, 7.43, 7.23, 6.83, 7.32, 7.56, 7.54, 7.47, 5.82, 6.78, 2.28, 6.32, 7.45, 7.65, 7.64, 7.36, 7.75, 7.80, 7.77, or 7.76; 
         preferably, the antibody-drug conjugate is any one of the following compounds: 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 for VH and an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 25 and a VL with an amino acid sequence as shown in SEQ ID NO: 26; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 15 and a VL with an amino acid sequence as shown in SEQ ID NO: 16; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a heavy chain with an amino acid sequence as shown in SEQ ID NO: 2 and a light chain with an amino acid sequence as shown in SEQ ID NO: 1; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a heavy chain with an amino acid sequence as shown in SEQ ID NO: 4 and a light chain with an amino acid sequence as shown in SEQ ID NO: 3; 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 22, and a VL with an amino acid sequence as shown in SEQ ID NO: 23; 
         or 
       
       
         
           
           
               
               
           
         
          wherein Ab is the anti-DLL3 antibody comprising a VH with an amino acid sequence as shown in SEQ ID NO: 45, and a VL with an amino acid sequence as shown in SEQ ID NO: 46. 
       
     
     
         14 . A chimeric antigen receptor comprising the anti-DLL3 antibody according to any one of  claims 1 to 6 . 
     
     
         15 . A genetically modified cell comprising the anti-DLL3 antibody according to any one of  claims 1 to 6 ; preferably, the genetically modified cell is a eukaryotic cell, preferably an isolated human cell; more preferably an immune cell such as a T cell, or NK cell. 
     
     
         16 . A preparation method for the anti-DLL3 antibody comprising following steps: cultivating the transformant according to  claim 9 , and obtaining the anti-DLL3 antibody from the culture. 
     
     
         17 . A pharmaceutical composition comprising the anti-DLL3 antibody according to any one of  claims 1 to 6 , the antibody-drug conjugate according to any one of  claims 10 to 13 , the chimeric antigen receptor according to  claim 14 , and/or the genetically modified cell according to  claim 15 ;
 preferably, the pharmaceutical composition is in a liquid, gas, solid, or semi-solid dosage formula, and/or, the pharmaceutical composition can be administered orally, by injection, nasally, transdermally, or via mucosal route;   more preferably, the pharmaceutical composition further comprises a combinational therapeutic agent comprising chemotherapeutic agents, radiation therapy agents, immunosuppressants, and/or cytotoxic drugs.   
     
     
         18 . A use of the anti-DLL3 antibody according to any one of  claims 1 to 6 , the antibody-drug conjugate according to any one of  claims 10 to 13 , the chimeric antigen receptor according to  claim 14 , the genetically modified cell according to  claim 15 , and/or the pharmaceutical composition according to  claim 17  in preparation of a medicament, a kit and/or a drug administration device for treatment and/or prevention of a disease related to abnormal expression of DLL3;
 the diseases related to abnormal expression of DLL3 is preferably tumor; the tumor is preferably cancer; the cancer is preferably neuroendocrine tumor, more preferably small cell lung cancer. 
 
     
     
         19 . A kit comprising the anti-DLL3 antibody according to any one of  claims 1 to 6 , the antibody-drug conjugate according to any one of  claims 10 to 13 , the chimeric antigen receptor according to  claim 14 , the genetically modified cell according to  claim 15 , and/or the pharmaceutical composition according to  claim 17 ; and optionally, an instruction manual. 
     
     
         20 . A drug administration device comprising: (1) an infusion module for administering the pharmaceutical composition according to  claim 17  to a subject in need thereof, and (2) optionally, a pharmacodynamic monitoring module. 
     
     
         21 . A method for detecting DLL3 comprising the step of using the anti-DLL3 antibody according to any one of  claims 1 to 6  for detection; preferably, the method is used for non-diagnostic and/or non-therapeutic purposes. 
     
     
         22 . A method for diagnosing, preventing and/or treating a disease related to abnormal expression of DLL3, comprising administering to a subject in need thereof with the anti-DLL3 antibody according to any one of  claims 1 to 6 , the antibody-drug conjugate according to any one of  claims 10 to 13 , the chimeric antigen receptor according to  claim 14 , the genetically modified cell according to  claim 15  and/or the pharmaceutical composition according to  claim 17 .